Immune Globulins for Post-Exposure Prophylaxis

Number: 0544

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Note: Requires Precertification:

Precertification of immune globulin human intramuscular injection (IGIM) (GamaSTAN) is required of all Aetna participating providers and members in applicable plan designs. For precertification of immune globulin human intramuscular injection (IGIM) (GamaSTAN), call (866) 752-7021 (Commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

Hepatitis B Immune Globulin

1. Criteria for Initial Approval

   1. Aetna considers hepatitis B immune globulin medically necessary for members who have had contact with an individual diagnosed with hepatitis B virus (HBV).  Risk groups include infants born to hepatitis B surface antigen (HBsAg)-positive mothers, persons with percutaneous or permucosal exposure to HbsAg-positive blood, sexual contacts of HbsAg-positive persons, and household exposure of infants less than 1 year of age to a primary caregiver with acute HBV infection.
   2. Aetna considers prolonged use of hepatitis B immune globulin medically necessary for prophylaxis of recurrent hepatitis B infection in HbsAg-positive liver transplant recipients.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of hepatitis B immune globulin therapy medically necessary for all members (including new members) who meet all initial medical necessity criteria.

Cytomegalovirus Immune Globulin

1. Criteria for Initial Approval

   Aetna considers cytomegalovirus (CMV) immune globulin (e.g., Cytogam) medically necessary for treatment of severe cytamegalovirus disease in transplant recipients, and for prophylaxis of CMV disease in CMV-negative renal transplant recipients receiving a CMV-positive donor organ, and for prophylaxis of CMV disease in lung, liver, pancreas, and heart transplant recipients receiving a CMV-positive donor.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of cytomegalovirus immune globulin therapy medically necessary for all members (including new members) who meet all initial medical necessity criteria.

3. Related Policies

   1. CPB 0206 - Parenteral Immunoglobulins.

Rho-D Immune Globulin

1. Criteria for Initial Approval

   1. Aetna considers Rho-D Immune Globulin (e.g., Gamulin Rh, HypRho-D Full Dose, HypRho-D Mini-Dose, MICRhoGAM, Mini-Gamulin Rh, Rhogam, and WinRho SDF) medically necessary for preventing hemolytic disease of the newborn.
   2. Rho-D immune globulin is considered medically necessary for all unsensitized Rh-negative women at 24 to 28 weeks gestation, unless the father is known to be Rh-negative.
   3. A repeat post-partum dose is considered medically necessary if a Rh-positive infant is delivered.
   4. Administration of Rho-D immune globulin is considered medically necessary in unsensitized Rh-negative women, unless the father is known to be Rh-negative, after other obstetric complications such as amniocentesis, chorionic villus sampling, ectopic pregnancy, pregnancy termination (including elective abortion), cordocentesis, fetal surgery or manipulation (including external version), antepartum placental hemorrhage, ante-partum fetal death, miscarriage and stillbirth.
   5. Rho-D immune globulin is also considered medically necessary for treatment of Rho-D positive persons with idiopathic thrombocytopenic purpura.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of Rho-D immune globulin therapy medically necessary for all members (including new members) who meet all initial medical necessity criteria.

Rabies Immune Globulin

1. Criteria for Initial Approval

   Aetna considers rabies immune globulin medically necessary for treatment of rabies exposure where the animal has escaped or is known to be rabid at the time of direct exposure or attackFootnote1*.

   Aetna considers rabies immune globulin medically necessary for post-exposure prophylaxis in the setting of a dog bite if the health status of the dog is unavailable.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of rabies immune globulin therapy medically necessary for all members (including new members) who meet all initial medical necessity criteria.

Varicella Zoster (Chickenpox) Immune Globulin

1. Criteria for Initial Approval

   1. Aetna considers varicella zoster immune globulin (VZIG) medically necessary for prevention of varicella (chickenpox) infections in high-risk individuals who have significant exposure to the disease due to contact with an individual who is infected with varicella, according to recommendations of the American Academy of Pediatrics.  High-risk individuals include immunocompromised persons without a history of chickenpox, susceptible pregnant women, newborn infants whose mother had onset of chickenpox within the 5 days before delivery or within 48 hours after delivery, hospitalized premature infants 28 or more weeks gestation whose mother has no history of chickenpox, and hospitalized premature infants less than 28 weeks gestation regardless of maternal history.  Significant exposures include household contacts of infected persons, face-to-face indoor play with infected persons, hospital contact with infected persons, and newborn infants whose mothers had onset of chickenpox near time of delivery (described above).
   2. Aetna considers post-exposure prophylaxis with varicella zoster immune globulin (VariZIG) as soon as possible within 10 days after exposure to a person with varicella or shingles medically necessary for HIV positive individuals who are susceptible to varicella zoster virus (those who have not been vaccinated, have no history of varicella or herpes zoster, or are seronegative for varicella zoster virus).

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of varicella zoster immune globulin (VZIG) therapy medically necessary for all members (including new members) who meet all initial medical necessity criteria.

Tetanus Immune Globulin

1. Criteria for Initial Approval

   Aetna considers intramuscular injection of tetanus immune globulin medically necessary for prevention of tetanus in non-immunized persons, incompletely immunized persons (who have not completed the 3-dose primary vaccination series), and remotely immunized persons (last complete vaccination more than 10 years ago) with neglected or tetanus-prone wounds (contaminated, necrotizing, or puncture wounds)Footnote1*.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of intramuscular injection of tetanus immune globulin therapy medically necessary for all members (including new members) who meet all initial medical necessity criteria.

Respiratory Syncytial Virus (RSV) Immune Globulin or Palivizumab

Related Policies

• CPB 0318 - Synagis (Palivizumab).

Vaccinia (Smallpox) Immune Globulin

1. Criteria for Initial Approval

   Aetna considers vaccinia immune globulin medically necessary for treatment of vaccine complications with severe clinical manifestations (e.g., eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, and severe ocular viral implantation).Footnote1*.

   Aetna considers vaccina immune globulin medically necessary for the treatment of monkeypox infection.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of vaccinia immune globulin therapy medically necessary for all members (including new members) who meet all initial medical necessity criteria.

3. Related Policies

   1. CPB 0644 - Smallpox Vaccine.

Infantile Botulism Immune Globulin

1. Criteria for Initial Approval

   Aetna considers botulism immune globulin intravenous human (BIG-IV) (BabyBIG) for the treatment of infant botulism caused by toxin types A or B in members below 1 year of age medically necessary.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of botulism immune globulin intravenous human (BIG-IV) (BabyBIG) therapy medically necessary for all members (including new members) who meet all initial medical necessity criteria.

Immune Globulin Human Intramuscular (IGIM) Injection (GamaSTAN)

1. Criteria for Initial Approval

   Aetna considers immune globulin intramuscular (IGIM) injection (GamaSTAN) medically necessary for the following indications:

   1. Prophylaxis of hepatitis A - Prophylaxis of hepatitis A when one of the following criteria is met:

      1. Member was exposed to hepatitis A virus within the past 2 weeks (e.g., household contact, sexual contact, and child care center or classroom contact with an infected person), and is not exhibiting clinical manifestation of disease; or
      2. Member is at high risk for hepatitis A exposure (examples of populations at high risk for hepatitis A are travelers to and workers in countries of high endemicity of infection and illicit drug users); or
         
   2. Prophylaxis of measles (rubeola) - Prophylaxis of measles (rubeola) in unvaccinated members who have not had measles previously and were exposed to measles within the past 6 days; or
      
   3. Prophylaxis of rubella - Prophylaxis of rubella when both of the following criteria are met:
      
      
      1. Member was recently exposed to rubella; and
      2. Member is currently pregnant; or
         

   4. Prophylaxis of varicella - Prophylaxis of varicella when all of the following criteria are met:

      1. Member was exposed to varicella within the past 10 days; and
      2. Member is at high risk for severe varicella (e.g., immunocompromised persons, newborns/infants, pregnant women); and
      3. Varicella zoster immune globulin (e.g., Varizig) is not available.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of immune globulin IM (IGIM) (GamaSTAN) therapy medically necessary for all members (including new members) requesting authorization who meet all initial medical necessity criteria.

Footnote1*Note: Treatment of work-related injuries is excluded from coverage under some benefit plans.  Please check benefit plan descriptions.  Work-related injuries may be covered by the employer's workman's compensation benefit plan.

Dosage and Administration

Immune globulin (human) intramuscular (IGIM) (GamaSTAN) is available as a sterile, 16.5% protein solution in 2 mL and 10 mL single-dose vials for intramuscular use only. Do not administer intravenously.

The recommending dosing for IGIM (GamaSTAN) is as follows:

Hepatitis A

Prophylaxis for exposure to hepatitis A

• Administer 0.1 mL/kg within two weeks of prior exposure for household and institutional hepatitis A case contacts.
• Administer before departure to persons traveling to areas with endemic hepatitis A:
  
  
  • 0.1 mL/kg if length of stay will end up to 1 month
  • 0.2 mL /kg if the length of stay wil be up to 2 months
  • 0.2 mL/kg if the length of stay will be 2 months or longer; repeat every 2 months.

Measles (Rubeola)

Prevent or modify measles in a susceptible person exposed fewer than six days previously:

• Administer 0.25 mL/kg to a susceptible person within 6 days of exposure
• Immediately administer 0.5 mL/kg (maximum dose, 15 mL) to an immunocompromised child.

Varicella

Modify varicella:

• Administer 0.6 mL/kg to 1.2 mL/kg promptly only if Varicella-Zoster Immune Globulin (Human) is unavailable.

Rubella

Modify rubella only in an exposed woman who will not consider a therapeutic abortion:

• Only administer 0.55 mL/kg to an exposed pregnant woman who will not consider a therapeutic abortion.

Source: Grifols Therapeutics, 2022

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Table:

CPT Codes / ICD-10 Codes / HCPCS Codes

Code	Code Description
Hepatitis A Immune Globulin:
CPT codes covered if selection criteria are met [no specific code]:
90281	Immune globulin (Ig), human, for intramuscular use
90399	Unlisted immune globulin
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J1460	Injection, gamma globulin, intramuscular, 1 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]
J1560	Injection, gamma globulin, intramuscular, over 10 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]
ICD-10 codes covered if selection criteria are met:
Z20.5	Contact with and (suspected) exposure to viral hepatitis
Z20.6	Contact with and (suspected) exposure to human immunodeficiency virus [HIV]
Z20.828	Contact with and (suspected) exposure to other viral communicable diseases
ICD-10 codes not covered for indications listed in the CPB:
B15.0	Hepatitis A with hepatic coma
B15.9	Hepatitis A without hepatic coma
Hepatitis B Immune Globulin:
CPT codes covered if selection criteria are met:
90371	Hepatitis B immune globulin (HBIg), human, for intramuscular use
HCPCS codes covered if selection criteria are met:
J1571	Injection, hepatitis B immune globulin (Hepagam B), intramuscular, 0.5 ml
J1573	Injection, hepatitis B immune globulin (Hepagam B), intravenous, 0.5 ml
ICD-10 codes covered if selection criteria are met:
Z20.5	Contact with and (suspected) exposure to viral hepatitis [Hepatitis B] [Not covered for prevention of mother -to-child transmission of hepatitis B virus during pregnancy]
Z48.23	Encounter for aftercare following liver transplant
Z57.8	Occupational exposure to other risk factors [exposure to potentially hazardous bodily fluids]
Z94.4	Liver transplant status
ICD-10 codes not covered for indications listed in the CPB:
B16.0 - B16.9 B18.0 - B18.1 B19.10 - B19.11	Hepatitis B
Z86.19	Personal history of other infectious and parasitic diseases [Not covered for prevention of mother -to-child transmission of hepatitis B virus during pregnancy]
Cytomegalovirus Immune Globulin:
CPT codes covered if selection criteria are met:
90291	Cytomegalovirus immune globulin (CMV-IgIV), human, for intravenous use
HCPCS codes covered if selection criteria are met:
J0850	Injection, cytomegalovirus immune globulin intravenous (human), per vial
ICD-10 codes covered if selection criteria are met:
B25.0 - B25.9	Cytomegaloviral disease
O35.3xx+	Maternal care for (suspected) damage to fetus from viral disease in mother [cytomegalovirus]
P35.1	Congenital cytomegalovirus infection
T86.00 - T86.99	Complications of transplanted organs and tissues
Z20.828	Contact with and (suspected) exposure to other viral communicable diseases [cytomegalovirus]
Z48.21 - Z48.298	Encounter for aftercare following organ transplant
Z94.0 - Z94.9	Transplanted organ and tissue status
ICD-10 codes not covered for indications listed in the CPB:
C88.0	Waldenstrom macroglobulinemia
D80.2	Selective deficiency of immunoglobulin A [IgA]
O98.811 - O98.83	Other maternal infectious and parasitic diseases complicating pregnancy, childbirth or puerperium [cytomegalovirus infection] [in utero]
Rho-D immune Globulin:
CPT codes covered if selection criteria are met:
90384	Rho(D) immune globulin (RHIg), human, full-dose, for intramuscular use
90385	Rho(D) immune globulin (RHIg), human, mini-dose, for intramuscular use
90386	Rho(D) immune globulin (RHIgIV), human, for intravenous use
Other CPT codes related to the CPB:
59000	Amniocentesis
59012	Cordocentesis (intrauterine), any method
59015	Chorionic villus sampling, any method
59072	Fetal umbilical cord occlusion, including ultrasound guidance
59074	Fetal fluid drainage (eg, vesicocentesis, thoracocentesis, paracentesis), including ultrasound guidance
59076	Fetal shunt placement, including ultrasonic guidance
59412	External cephalic version, with or without tocolysis
59812 - 59857	Abortion
HCPCS codes covered if selection criteria are met:
J2788	Injection, Rho D immune globulin, human, minidose, 50 mcg
J2790	Injection, Rho D immune globulin, human, full dose, 300 mcg
J2791	Injection, Rho D immune globulin, human (Rhophylac), intramuscular or intravenous, 10 IU
J2792	Injection, Rho D immune globulin, intravenous, human, solvent detergent, 100 IU
ICD-10 codes covered if selection criteria are met:
D69.3	Immune thrombocytopenia purpura
O00.00 - O00.91	Ectopic pregnancy
O02.1	Missed abortion
O03.0 - O03.9	Spontaneous abortion
O36.4xx0 - O36.4xx9	Maternal care for intrauterine death
O44.10 - O44.13	Hemorrhage from placenta previa
O45.001 - O45.93	Premature separation of placenta [abruptio placentae]
Rabies Immune Globulin:
CPT codes covered if selection criteria are met:
90375	Rabies immune globulin (RIg), human, for intramuscular and/or subcutaneous use
90376	Rabies immune globulin, heat-treated (RIg-HT), human, for intramuscular and/or subcutaneous use
90377	Rabies immune globulin, heat- and solvent/detergent-treated (RIg-HT S/D), human, for intramuscular and/or subcutaneous use
ICD-10 codes covered if selection criteria are met:
Z20.3	Contact with and (suspected) exposure to rabies [dog bite]
Varicella Zoster Immune Globulin:
CPT codes covered if selection criteria are met:
90281	Immune globulin (Ig), human, for intramuscular use
90396	Varicella-zoster immune globulin, human, for intramuscular use
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J1460	Injection, gamma globulin, intramuscular, 1 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]
J1560	Injection, gamma globulin, intramuscular, over 10 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]
ICD-10 codes covered if selection criteria are met:
B20	Human immunodeficiency virus [HIV] disease
Z20.820	Contact with and (suspected) exposure to varicella
Tetanus Immune Globulin:
CPT codes covered if selection criteria are met:
90389	Tetanus immune globulin (TIg), human, for intramuscular use
HCPCS codes covered if selection criteria are met:
J1670	Injection tetanus immune globulin, human, up to 250 units
ICD-10 codes covered if selection criteria are met:
M72.6	Necrotizing fasciitis
T20.00x+ - T25.799+	Burns and corrosions of external body surface, specified by site [contaminated, necrotizing]
Numerous options	Open wound [complicated only] [contaminated, necrotizing, puncture] [Codes not listed due to expanded specificity]
Numerous options	Superficial injury [infected only] [contaminated, necrotizing, puncture] [Codes not listed due to expanded specificity]
Rubeola (Measles) Immune Globulin:
CPT codes covered if selection criteria are met [no specific code]:
90281	Immune globulin (Ig), human, for intramuscular use
90399	Unlisted immune globulin
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J1460	Injection, gamma globulin, intramuscular, 1 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]
J1560	Injection, gamma globulin, intramuscular, over 10 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]
ICD-10 codes covered if selection criteria are met:
Z20.828	Contact with and (suspected) exposure to other viral communicable diseases [rubeola (measles)]
Immune Globulin for German Measles (Rubella):
CPT codes covered if selection criteria are met [no specific code]:
90281	Immune globulin (Ig), human, for intramuscular use
90399	Unlisted immune globulin
HCPCS codes covered if selection crieria are met:
J1460	Injection, gamma globulin, intramuscular, 1 cc
J1560	Injection, gamma globulin, intramuscular, over 10 cc
ICD-10 codes covered if selection criteria are met:
Z20.4	Contact with and (suspected) exposure to rubella
Immune Globulin (IGIM) for German Measles (Rubella):
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered for conditions listed in the CPB:
J1460	Injection, gamma globulin, intramuscular, 1 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]
J1560	Injection, gamma globulin, intramuscular, over 10 cc [GamaSTAN and GamaSTAN S/D (formerly BayGam)]
ICD-10 codes covered if selection criteria are met:
Z20.4	Contact with and (suspected) exposure to rubella
Vaccinia (Smallpox) Immune Globulin:
CPT codes covered if selection criteria are met:
90393	Vaccinia immune globulin, human, for intramuscular use
ICD-10 codes covered if selection criteria are met:
B04	Monkeypox
T88.1xx+	Other complications following immunization, not elsewhere classified
Z20.828	Contact with and (suspected) exposure to other viral ncommunicable diseases [vaccinia (smallpox)]
ICD-10 codes contraindicated for this CPB:
H16.001 - H16.9	Keratitis
Infantile Botulism Immune Globulin:
CPT codes covered if selection criteria are met:
90288	Botulism immune globulin, human, for intravenous use [BabyBIG or BIG-IV]
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure)
ICD-10 codes covered if selection criteria are met:
A48.51	Infant botulism

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Immune globulin (human) intramuscular injection (GamaSTAN)

GamaSTAN is a human immune globulin indicated for:

• Hepatitis A

  GamaSTAN is indicated for prophylaxis following exposure to hepatitis A. The prophylactic value of GamaSTAN is greatest when given before or soon after exposure to hepatitis A. GamaSTAN is not indicated in persons with clinical manifestations of hepatitis A or in those exposed more than 2 weeks previously.

• Measles (Rubeola)

  GamaSTAN is indicated to prevent or modify measles in a susceptible person exposed fewer than 6 days previously. A susceptible person is one who has not been vaccinated and has not had measles previously.

  • GamaSTAN may be especially indicated for susceptible household contacts of measles patients, particularly contacts under 1 year of age, for whom the risk of complications is highest.
  • GamaSTAN is also indicated for pregnant women without evidence of immunity.
  • Do not give GamaSTAN and measles vaccine at the same time. If a child is older than 12 months and has received GamaSTAN, give measles vaccine about five months later when the measles antibody titer will have disappeared.
  • If a susceptible child exposed to measles is immunocompromised, give GamaSTAN immediately.
    
    

• Varicella

  GamaSTAN is indicated to modify varicella.

  • Passive immunization against varicella in immunosuppressed patients is best accomplished by use of Varicella Zoster Immune Globulin (Human). If unavailable, GamaSTAN, promptly given, may also modify varicella.

• Rubella

  GamaSTAN is indicated to modify rubella in exposed women who will not consider a therapeutic abortion.

  • Some studies suggest that the use of GamaSTAN in exposed, susceptible women can lessen the likelihood of infection and fetal damage; therefore, GamaSTAN may benefit those women who will not consider a therapeutic abortion.
  • Do not give GamaSTAN for routine prophylaxis of rubella in early pregnancy to an unexposed woman.

Limitations of Use:

• GamaSTAN is not standardized with respect to antibody titers against hepatitis B surface antigen (HBsAg) and must not be used for prophylaxis of viral hepatitis type B. Prophylactic treatment to prevent hepatitis B can best be accomplished with use of Hepatitis B Immune Globulin (Human), often in combination with Hepatitis B Vaccine.
• GamaSTAN is not indicated for routine prophylaxis or treatment of rubella, poliomyelitis, mumps, or varicella.

Note: Immune globulin (human) intramuscular injection (GamaSTAN S/D) has been discontinued by Grifols Therapeutics, Inc.

Cytomegalovirus Immune Globulin

Cytogam (cytomegalovirus immune globulin, human) is a purified immune globulin, IgG, derived from pooled adult human serum selected for high titers of antibody to cytomegalovirus (CMV). The pooled plasma is fractionated to yield a product suitable for intravenous administration and further subjected to a solvent‐detergent viral inactivation process. The globulin is stabilized with 5% sucrose and 1% human albumin.

Cytomegalovirus Immune Globulin IV (CMV-Ig) contains antibodies directed specificially towards cytomegalovirus (CMV), which is generally present in persons who have been exposed to the virus.  While CMV is quite prevalent in adults and is typically benign in healthy people, it is a significant cause of morbidity and mortality in people who are immunosuppressed due to organ transplantation or AIDS. Cytomegalovirus immune globulin human can raise the serum titer of antibodies against CMV to sufficient levels to attenuate or reduce the occurrence of serious CMV infection.

Cytomegalovirus Immune Globulin IV is currently approved by the Food and Drug Administration (FDA) for use in prophylaxis of CMV disease in kidney, heart, lung, pancreas and liver transplant patients.  It also has been shown to be beneficial in prevention and treatment of CMV disease in patients who have received an orthotopic liver transplant.  There is also evidence for use of CMV-Ig in other solid organ transplants (such as heart and lung) and in bone marrow transplants.

Studies in renal transplantation have generally been limited to patients who are CMV sero-negative; use in sero-positive recipients therefore remains investigational.  This is not the case with other transplants; in fact, results in liver transplant patients have shown a decrease in severe CMV-associated syndromes.

CMV is the primary viral pathogen that will be encountered by members who receive kidney, liver, pancreas, lung, and heart transplants. CMV is associated with increases in morbidity, including fever, leukopenia, hepatitis, pneumonia, and CMV retinitis. Administration of cytomegalovirus immunoglobulin has been associated with a significant decrease in CMV‐related morbidity from 60% to 21% in renal transplant recipients. Similar findings have been reported in liver transplant recipients with the incidence of serious CMV disease significantly decreasing from 26% to 12%.

It has been reported that combination prophylaxis with ganciclovir has produced results demonstrating much lower incidence of CMV infection than either drug alone. Specifically, in liver transplant patients combination with ganciclovir significantly decreased the incidence of severe CMV infection from 28% to 5% when compared to monotherapy with CMV immune globulin. Rates of serious CMV infection of 1%, 0%, and 8% were demonstrated with combination therapy in kidney, kidney‐pancreas, and liver transplant recipients, respectively. In heart, heart‐lung, and lung transplant recipients, incidence rates decreased significantly when cytomegalovirus immune globulin was added to ganciclovir prophylaxis and overall survival rates increased significantly.

Members with a history of severe reactions to cytomegalovirus immune globulin or other human immunoglobulin preparations should not receive Cytogam.

Dosage Adjustments:

No recommendations for dosage adjustments

Test/Lab Justifications:

• Anti‐neutrophil antibodies if Transfusion‐related Acute Lung Injury suspected
• Blood viscosity testing for members at high risk of thrombosis (cryoglobulins, fasting chylomicronemia/markedly high triglycerides, or monoclonal gammopathies)
• Hemolysis testing if hemolysis is suspected.

In a retrospective analysis, Buxmann et al (2012) examined the current prenatal "off-label use" of CMV-hyperimmune globulin (CMV-HIG) in the prevention and treatment of congenital CMV (cCMV) infection, including the long-term outcome of the children.  This retrospective observational study comprised mothers and their children, born between January 1, 2006, and October 30, 2010.  Prenatal CMV-HIG was administered after diagnosis of primary CMV infection of the mother.  Clinical and virological data were collected from maternal and pediatric medical and laboratory reports.  Follow-up was 12 to 36 months after birth.  A total of 42 women and 43 children met the study criteria.  In total, 40 mothers and 6 unborn infants received 115 doses of CMV-HIG.  The treatment group (TG; CMV-DNA polymerase chain reaction-positive amniotic fluid) included 4 mothers; the multi-nomial group (MG; CMV-positive mother and unknown CMV status of fetus) included 38 mothers (39 infants).  For the 4 unborn infants in TG, CMV-HIG was administered either intra-umbilically or into the amniotic fluid; 3 of the 4 mothers received intravenous CMV-HIG.  Three children in TG remained CMV-positive and were asymptomatic at birth and during follow-up.  One infant in TG had symptomatic cCMV infection in-utero, at birth, and during follow-up.  In MG, 37 of 38 women received intravenous CMV-HIG and 2 of 39 infants received CMV-HIG in-utero.  In total, 9 (23.1 %) of 39 children in MG were positive for cCMV (including a terminated pregnancy).  All 8 instances of cCMV infection at birth in MG were asymptomatic at birth and during follow-up.  The fetus from the terminated pregnancy showed no sonographic symptoms of cCMV infection.  No severe side effect occurred in 115 CMV-HIG applications.  The authors concluded that CMV-HIG was well-tolerated.  Compared with published untreated mother-child pairs, the authors observed a trend toward a smaller risk for intrauterine CMV transmission following CMV-HIG application.  Signs of prenatal cCMV disease were not reversed after CMV-HIG.

Simioni et al (2013) stated that primary CMV infection during pregnancy is the leading infectious cause of congenital neurological disabilities.  Diagnosis of maternal primary CMV infection and fetal compromise can be difficult, as well as the fact that most infected child are asymptomatic at birth, which makes binomial CMV and pregnancy challenging.  The treatment of pregnant women with CMV-HIG has shown promising results.  However, as far as the authors knew, no randomized trials of immunoglobulin therapy of CMV-infected fetuses are ongoing. 

An UpToDate review on “Cytomegalovirus infection in pregnancy” (Boppana, 2023) states that "CMV hyperimmune globulin therapy should only be used in a research setting until more data are available".

In a phase II, randomized, placebo-controlled, double-blind study, Revello et al (2014) evaluated the effectiveness of hyperimmune globulin in the prevention of congenital cytomegalovirus.  A total of 124 pregnant women with primary CMV infection at 5 to 26 weeks of gestation were randomly assigned within 6 weeks after the presumed onset of infection to receive hyperimmune globulin or placebo every 4 weeks until 36 weeks of gestation or until detection of CMV in amniotic fluid.  The primary end- point was congenital infection diagnosed at birth or by means of amniocentesis.  A total of 123 women could be evaluated in the effectiveness analysis (1 woman in the placebo group withdrew).  The rate of congenital infection was 30 % (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44 % (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95 % confidence interval [CI]: -3 to 31; p = 0.13).  There was no significant difference between the 2 groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell-mediated immune response, or viral DNA in the blood.  The clinical outcome of congenital infection at birth was similar in the 2 groups.  The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13 % versus 2 %).  The authors concluded that in this study involving 123 women who could be evaluated, treatment with hyperimmune globulin did not significantly modify the course of primary CMV infection during pregnancy.  Moreover, they stated that “From the cost-effectiveness point of view, our results (a 32 % relative decrease in the transmission rate and no significant difference in the clinical outcome at birth) represent less than the 47 % reduction in congenital CMV that has been considered by some to be the threshold for recommending screening for and treatment of primary maternal infection in pregnancy as a cost-effective strategy.  Currently, two randomized, phase 3 studies of the prevention of congenital infection are under way.  One, sponsored by Biotest, is being conducted in Europe, and the second, sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, is ongoing in the United States (ClinicalTrials.gov number, NCT01376778).  The hope is that the results of these studies will further our understanding of the efficacy and safety of hyperimmune globulin administration as a means of preventing congenital CMV infection”.

Cytomegalovirus immune globulin, human is available as Cytogam in 2500 mg ± 500 mg per 50 mL (50 ± 10 mg/mL) vials.

Dosing:

• Cytomegalovirus infection; Prophylaxis ‐ Transplant of heart, liver, pancreas, lung: 150 mg/kg IV within 72 hours of transplant and on weeks 2,4,6, and 8 post transplant and 100 mg/kg on weeks 12 and 16 post transplant
• Cytomegalovirus infection; Prophylaxis ‐ Transplant of kidney: 150 mg/kg IV for 1 dose within 72 hours of transplant then 100 mg/kg on weeks 2,4,6, and 8 post transplant and 50 mg/kg on weeks 12 and 16 post transplant.

Hepatitis B Immune Globulin

Hepatitis B immune globulin is appropriate when used to provide passive immunization to hepatitis B as prophylaxis for certain exposed individuals.  The Advisory Committee on Immunization Practices (ACIP) states that combined passive and active immunization is preferred to passive immunization with HBIg alone in neonates born to HBsAb-positive women, in individuals exposed percutaneously or by ingestion or mucous membrane contact, and in individuals bitten by human carriers of HBsAG.  Also, combined treatment is recommended for patients exposed through sexual contact.  Hepatitis B immune globulin is administered promptly after exposure and again in 1 month.

Hepatitis B immune globulin is also indicated for prophylaxis of recurrent hepatitis B infection in HbsAg-positive liver transplant recipients.  Hepatitis B immune globulin prophylaxis is administered on a lifelong or indefinite basis for this indication.

The manufacturers state that the intra-muscular (IM) product is not to be used in an intravenous (IV0 fashion.  This is apparently because "serious systemic allergic reactions could occur following inadvertent IV administration of HBIg, since such reactions have occurred following IV administration of immune globulin".  Since it appears that the contraindication to IV use is theoretical, and that IV use is occurring without safety problems, it is appropriate to allow IV use when IM is not an option.

Rao and colleagues (2009) performed a systematic review and a meta-analysis to evaluate lamivudine monotherapy and combined therapy of lamivudine and hepatitis B immunoglobulin (HBIG) in hepatitis B virus (HBV) infected liver recipients.  A fixed effects model was used for statistical pooling of relative risks (RR) for the different outcomes.  Six articles (n = 551) fulfilled the inclusion criteria.  Statistically significant differences were observed between lamivudine monotherapy and lamivudine + HBIG therapy in hepatitis B recurrence (p < 0.0001; RR = 0.38; 95 % CI: 0.25 to 0.58), YMDD mutant (p = 0.002; RR = 0.40; 95 % CI: 0.23 to 0.72) and hepatitis B recurrence in HBV-DNA positive patients before orthotopic liver transplantation (p < 0.00001; RR = 0.31; 95 % CI: 0.21 to 0.45).  No significant differences were observed in patient survival (p = 0.59; RR = 1.02; 95 % CI: 0.95 to 1.09), graft survival (p = 0.56; RR = 1.02; 95 % CI: 0.95 to 1.09) and diseases leading to death between the 2 groups (HBV recurrence leading to death: p = 0.05; RR = 0.47; 95 % CI: 0.22 to 1.02); hepatocellular carcinoma recurrence leading to death: p = 0.13; RR = 0.34; 95 % CI: 0.09 to 1.36).  The authors concluded that combination of lamivudine and HBIG can effectively decrease the recurrence rate of HBV and the incidence of YMDD mutant, but it can not improve patient survival and graft survival significantly.  They stated that well-designed, large-sample trials are needed to evaluate the efficiency of combined therapy of lamivudine and HBIG in prophylaxis of HBV recurrence in liver graft recipients.

For Use During Pregnancy for Prevention of Mother-to-Child Transmission of Hepatitis B Virus

Eke and colleagues (2017) stated that hepatitis is a viral infection of the liver.  It is mainly transmitted between people through contact with infected blood, frequently from mother to baby in-utero.  Hepatitis B poses significant risk to the fetus and up to 85 % of infants infected by their mothers at birth develop chronic HBV infection; HBIG is a purified solution of human immunoglobulin that could be administered to the mother, newborn, or both; HBIG offers protection against HBV infection when administered to pregnant women who test positive for hepatitis B envelope antigen (HBeAg) or hepatitis B surface antigen (HBsAg), or both.  When HBIG is administered to pregnant women, the antibodies passively diffuse across the placenta to the child.  This materno-fetal diffusion is maximal during the 3rd trimester of pregnancy.  Up to 1 % to 9 % infants born to HBV-carrying mothers still have HBV infection despite the newborn receiving HBIG plus active HBV vaccine in the immediate neonatal period.  This suggests that additional intervention such as HBIG administration to the mother during the antenatal period could be beneficial to reduce the transmission rate in utero.  In a Cochrane review, these researchers determined the benefits and harms of HBIG administration to pregnant women during their 3rd trimester of pregnancy for the prevention of mother-to-child transmission (MTCT) of HBV infection.  They searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, Medline Ovid, Embase Ovid, Science Citation Index Expanded (Web of Science), SCOPUS, African Journals OnLine, and INDEX MEDICUS up to June 2016.  They searched ClinicalTrials.gov and portal of the WHO International Clinical Trials Registry Platform (ICTRP) in December 2016.  These researchers included randomized clinical trials comparing HBIG versus placebo or no intervention in pregnant women with HBV.  Two authors extracted data independently.  They analyzed dichotomous outcome data using risk ratio (RR) and continuous outcome data using mean difference (MD) with 95 % CI.  For meta-analyses, these investigators used a fixed-effect model and a random-effects model, along with an assessment of heterogeneity.  If there were statistically significant discrepancies in the results, they reported the more conservative point estimate.  If the 2 estimates were equal, these researchers used the estimate with the widest CI as their main result.  They assessed bias control using the Cochrane Hepato-Biliary Group suggested bias risk domains and risk of random errors using Trial Sequential Analysis (TSA); and assessed the quality of the evidence using GRADE.  All 36 included trials originated from China and were at overall high risk of bias.  The trials included 6,044 pregnant women who were HBsAg, HBeAg, or HBV-DNA positive.  Only 7 trials reported inclusion of HBeAg-positive mothers.  All 36 trials compared HBIG versus no intervention.  None of the trials used placebo.  Most of the trials assessed HBIG 100 IU (2 trials) and HBIG 200 IU (31 trials).  The timing of administration of HBIG varied; 30 trials administered 3 doses of HBIG 200 IU at 28, 32, and 36 weeks of pregnancy.  None of the trials reported all-cause mortality or other serious adverse events (AEs) in the mothers or babies.  Serological signs of hepatitis B infection of the newborns were reported as HBsAg, HBeAg, and HBV-DNA positive results at end of follow-up; 29 trials reported HBsAg status in newborns (median of 1.2 months of follow-up after birth; range 0 to 12 months); 7 trials reported HBeAg status (median of 1.1 months of follow-up after birth; range 0 to 12 months); and 16 trials reported HBV-DNA status (median of 1.2 months of follow-up; range 0 to 12 months); HBIG reduced MTCT of HBsAg when compared with no intervention (179/2,769 (6 %) with HBIG versus 537/2,541 (21 %) with no intervention; RR 0.30, TSA-adjusted CI: 0.20 to 0.52; I2 = 36 %; 29 trials; 5,310 participants; very low quality evidence); HBV-DNA reduced MTCT of HBsAg (104/1,112 (9 %) with HBV-DNA versus 382/1,018 (38 %) with no intervention; RR 0.25, TSA-adjusted CI: 0.22 to 0.27; I2 = 84 %; 16 trials; 2,130 participants; low quality evidence); TSA supported both results.  Meta-analysis showed that maternal HBIG did not decrease HBeAg in newborns compared with no intervention (184/889 (21 %) with HBIG versus 232/875 (27 %) with no intervention; RR 0.68, TSA-adjusted CI: 0.04 to 6.37; I2 = 90 %; 7 trials; 1,764 participants; very low quality evidence); TSA could neither support nor refute this observation as data were too sparse.  None of the trials reported AEs of the immunoglobulins on the newborns, presence of local and systemic AEs on the mothers, or cost-effectiveness of treatment.  The authors concluded that due to very low to low quality evidence found in this review, they are uncertain of the effect of benefit of antenatal HBIG administration to the HBV-infected mothers on newborn outcomes, such as HBsAg, HBV-DNA, and HBeAg compared with no intervention.  They stated that the results of the effects of HBIG on HBsAg and HBeAg are surrogate outcomes (raising risk of indirectness), and one need to be critical while interpreting the findings.  These investigators found no data on newborn mortality or maternal mortality or both, or other serious AEs.  They stated that well-designed randomized clinical trials are needed to determine the benefits and harms of HBIG versus placebo in prevention of MTCT of HBV.

Furthermore, an UpToDate review on “Hepatitis B and pregnancy” (Lee and Lok, 2023) does not mention the use of HBIG during pregnancy as a management tool.

Hepatitis A Immune Globulin

Hepatitis A immune globulin is indicated for persons who are exposed or likely to be exposed to hepatitis A virus (HAV).  Risk groups include household and sexual contacts of persons with hepatitis A, newborn infants of HAV-infected mothers, staff and children at child-care centers and schools with HAV outbreaks, staff of custodial care institutions with HAV outbreaks, and individuals exposed to HAV through food or water-borne outbreaks.  The usual dose is a single IM injection administered within 2 weeks of exposure.

Rho-D Immune Globulin

Rhogam is a specially prepared immune globulin injected into an Rh-negative mother to prevent Rh hemolytic disease in future children.  Rho-D immune globulin may be indicated for prevention of Rh hemolytic disease in neonates by administration to selected pre-menopausal, Rho-D-negative females; and for treatment of selected Rho-D-positive patients with ITP.

Administration of Rhogam is recommended under generally accepted guidelines for all unsensitized Rh-negative women at 24 to 28 weeks gestation, unless the father is known to be Rh-negative.  If a Rh-positive infant is delivered, accepted guidelines indicate the dose should be repeated post-partum, preferably within 72 hours of delivery.  The American College of Obstetricians and Gynecologists recommends administration of Rhogam after other obstetric complications such as amniocentesis, chorionic villus sampling, ectopic pregnancy, pregnancy termination, cordocentesis, fetal surgery or manipulation (including external version), ante-partum placental hemorrhage, ante-partum fetal death, miscarriage and stillbirth.  The literature indicates this immune globulin may also be used for treatment of selected Rho-D-positive persons with idiopathic thrombocytopenic purpura.  Under generally accepted guidelines, Rhogam is recommended for all unsensitized Rh-negative women after elective abortion, unless the father is known to be Rh-negative.

WinRho may be administered intramuscularly or intravenously over 3 to 5 mins.  Other brands are indicated for IM use.  Intramuscular injection is a relative contraindication in patients with ITP; however, has been used with some success.  While some feel that use of this product for treatment of ITP may not be effective in splenectomized patients, others provide evidence to the contrary.  When given in conjunction with pregnancy, Rho-D immune globulin does not provide benefit for the infant from that pregnancy.  Its use is intended to prevent Rh hemolytic disease in future infants born to that mother.

Varicella Zoster Immune Globulin

Varizig (varicella zoster immune globulin) is a solvent/detergent‐treated sterile lyophilized preparation of purified human immune globulin G (IgG) containing antibodies to varicella zoster virus (anti-VZV). Varizig (varicella zoster immune globulin) provides passive immunization for nonimmune individuals exposed to VZV, reducing the severity of varicella infections.

Varicella zoster virus (VZV) causes chickenpox in children and shingles in adults. Varizig is the only FDA approved immune globulin for VZV after exposure available in the United States. It was designated as an orphan drug by the FDA and received a priority review.

Varicella zoster immune globulin (VZIG) is considered appropriate when used to prevent varicella (chickenpox) infection as recommended by the ACIP.  According to the ACIP, VZIG is necessary, provided that significant exposure has occurred for immunocompromised children without a history of chickenpox.  Immuocompromised adolescents and adults are likely to be immune, but if susceptible, should also receive VZIG.  Varicella zoster immune globulin is also necessary, provided that significant exposure has occurred, for the following groups; susceptible pregnant women; newborn infants whose mother had onset of chickenpox within the 5 days before delivery or within the 48 hours after delivery; hospitalized premature infants (greater than or equal to 28 weeks gestation) whose mother has no history of chickenpox; and hospitalized premature infants (less than 28 weeks of gestation or less than or equal to 1,000 grams) regardless of maternal history.

Varicella zoster immune globulin may be indicated in the above listed susceptible groups if significant exposure to varicella has occurred in the hospital: in the same 2- to 4-bed room, or adjacent beds in a large ward; face-to-face contact with an infectious staff memeber or patient, or visit by a person deemed contageous.  Experts differ in the duration of face-to-face contact that warrants the administration of VZIG.  Some experts suggest a contact of 5 or more mins as constituting significant exposure for this purpose; others define close contact as more than 1 hour.  In any case, the face-to-face contact should be non-transient to be considered significant.

Other types of exposure for which VZIG is indicated in the above listed susceptible groups include: household exposure (residing in the same household); exposure from playmates (face-to-face indoor play); and intimate contact with zoster lesions (e.g., touching or hugging a person deemed contageous; and exposure of newborn infant (onset of varicella in the mother 5 days or less before delivery or within 48 hours after delivery; VZIG is not indicated if the mother has zoster).  The ACIP recommends that VZIG be administered within 96 hours of exposure

Laboratory determination of susceptibility to varicella is sometimes impractical.  Because of this, the ACIP recommends that determination of susceptibility be based on a carefully obtained history of prior infection or exposure.  However, in the case of pregnant women, serologic status should be determined through immunofluorescent assay or ELISA test if results can be available within 96 hours of exposure.  If this test is feasible and negative, immune globulin need not be given.  Otherwise, pregnant women should be considered susceptible.

Varicella zoster immune globulin is not necessary in individuals who are considered to be immune to varicella zoster.  With the exception of bone marrow transplant recipients, individuals considered to be immune to varicella zoster include those with a history of prior varicella infection, or negative or uncertain exposure if they are at least 15 years of age and immunocompetent.  In addition, patients with a history of infection with varicella or herpes zoster subsequent to bone marrow transplant are considered to be immune.

There is currently no evidence that administration of VZIG to pregnant women during the first or second trimester of pregnancy will prevent congenital varicella syndrome or that administration during the third trimester will prevent neonatal varicella.  In addition, post-exposure administration of VZIG in susceptible, pregnant women may prevent or suppress clinical disease in the mother without preventing fetal infection or disease.  For this reason, administration of VZIG for pregnant women who do not fit the criteria listed above is not considered to be necessary.

VariZIG (Cangene Corporation, Winnipeg, Canada) is the only VZIG preparation available in the United States for post-exposure prophylaxis of varicella in persons at high-risk for severe disease who lack evidence of immunity to varicella and are ineligible for varicella vaccine.  VariZIG is available in the United States through an investigational new drug (IND) application expanded access protocol.  It is a purified immune globulin preparation made from human plasma containing high levels of anti-varicella zoster virus antibodies (immunoglobulin G).  In May 2011, the FDA approved an extended period for administering VariZIG.  The period after exposure to varicella zoster virus during which a patient may receive VariZIG, which had been 96 hours (4 days), is now 10 days.  VariZIG should be administered as soon as possible after exposure (CDC, 2012).

Varicella zoster immune globulin is available as:

• Varizig in a single‐use vial of 125 IU Lyophilized Powder for Solution for Injection. Varizig is accompanied by a vial of 8.5 mL of sterile diluent used for reconstitution. Each vial of Varizig is reconstituted with 1.25 mL of sterile diluent.
• Varizig Sterile Solution for Injection. Varizig is supplied as a sterile solution for intramuscular injection and is available in a single‐use vial of 125 IU in 1.2 mL.

Varizig (varicella zoster immune globulin) is administered as an intramuscular injection. The minimum dose of Varizig is 62.5 IU (1 vial) for small infants under two kilograms body weight. The maximum dose of 625 IU (5 vials) should be administered for all patients greater than 40 kilograms in weight. Consider a second full dose of Varizig for high risk patients who have additional exposures to varicella greater than three weeks after initial Varizig administration.

Varizig administration is intended to reduce the severity of varicella. Administer Varizig as soon as possible following varicella zoster virus (VZV) exposure, ideally within 96 hours for greatest effectiveness. There is no convincing evidence that Varizig reduces the incidence of chickenpox infection after exposure to VZV. There is no convincing evidence that established infections with VZV can be modified by Varizig administration. There is no indication for the prophylactic use of Varizig in immunodeficient children or adults when there is a past history of varicella, unless the patient is undergoing bone marrow transplantation.

Contraindications

• Individuals known to have anaphylactic or severe systemic (hypersensitivity) reactions to human immune globulin preparations should not receive Varizig.
• IgA-deficient patients with antibodies against IgA and a history of hypersensitivity may have an anaphylactoid reaction. Varizig contains less than 40 micrograms per milliliter of IgA.

Dosage and Administration

Table: Dosage and Administration

Weight of Patient (Kilograms)	Weight of Patient (Pounds)	Varizig Dose (IU)	Number of Vials	Volume to AdministerFootnote2** (milliliters)
≤ 2.0	≤ 4.4	62.5	0.5	0.6
2.1 - 10.0	4.5 - 22.0	125	1	1.2
10.1 - 20.0	22.1 - 44.0	250	2	2.4
20.1 - 30.0	44.1 - 66.0	375	3	3.6
30.1 - 40.0	0 66.1 - 88.0	500	4	4.8
≥ 40.1	≥ 88.1	625	5	6.0

Footnote2**Extractable volumes are confirmed using a 21 gauge needle as per USP General Chapters <1> Injections.

Aberg et al (2014) reported on the 2013 update on primary care guidelines for management of HIV infected persons by the HIV Medicine Association of the Infectious Diseases Society of America.  New information based on literature published from 2009 to 2013 was incorporated into this updated version of the guidelines.  The guidelines make a strong recommendation, based on moderate quality evidence, that HIV positive patients who have not been vaccinated, have no history of varicella or herpes zoster, or are sero-negative for varicella zoster virus, and are thus susceptible to varicella zoster virus should receive post-exposure prophylaxis.  The post-exposure prophylaxis should consist of varicella zoster immune globulin (VariZIG) as soon as possible but within 10 days after exposure to a person with varicella or shingles.  The recommendations further noted that varicella primary vaccination may be considered in HIV-infected, varicella zoster virus seronegative persons aged > 8 years with CD4 cell coungs > 200 cells / microliter and in HIV-infected children aged 1 to 8 years with CD4 cell percentages > 15% due to moderate quality evidence in the peer-reviewed literature.

Levin and colleagues (2019) stated that despite vaccination, there were more than 100,000 annual cases of varicella in the U.S. in 2013 to 2014.  Individuals at highest risk of developing severe or complicated varicella include immunocompromised people, preterm infants, and pregnant women.  Varicella zoster immune globulin (human) (VARIZIG) is recommended by the CDC for post-exposure prophylaxis to prevent or attenuate varicella-zoster virus infection in high-risk individuals.  Contemporary information on administration of VARIZIG is limited.  An open-label, expanded-access program provided VARIZIG to physician-identified, high-risk participants exposed to varicella.  Subjects included immunocompromised children/adults, infants (preterm, newborns whose mothers had varicella onset within 5 days before or 2 days after delivery, and those aged less than 1 year), and pregnant women.  VARIZIG (125 IU/10 kg [up to 625 IU]) was administered intramuscularly, ideally within 96 hours, but up to 10 days, post-exposure.  Incidence of varicella rash and severity (greater than 100 pox, pneumonia, or encephalitis) were assessed up to 42 days after administration.  The varicella outcome population (n = 507) included 263 immunocompromised subjects (32 adults, 231 children), 137 pregnant women, 105 infants, and 2 healthy adults with no history of varicella.  Varicella incidence was 4.5 % in immunocompromised subjects, 7.3 % in pregnant women, and 11.5 % in infants.  The incidence of varicella was similar when comparing VARIZIG administration less than or equal to 96 hours versus greater than 96 hours (up to 10 days) post-exposure in the entire population (6.2 % versus 9.4 %, respectively), and also in each subgroup.  Of 34 subjects with varicella, 5 developed greater than 100 pox and 1 developed pneumonia and encephalitis.  There were no product-related deaths and only 1 serious AE (serum sickness) considered probably related to VARIZIG.  The authors concluded that post-exposure administration of VARIZIG was associated with low rates of varicella in high-risk participants, regardless of when administered within 10 days post-exposure; VARIZIG was safe and well-tolerated in high-risk subjects.

Vaccinia (Smallpox) Immune Globulin

Vaccinia vaccine is indicated for treatment of vaccine complications with severe clinical manifestations (e.g., eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, and severe ocular viral implantation).  The only product currently available for treatment of complications of vaccinia vaccination is vaccinia immunoglobulin, which is an isotonic sterile solution of the immunoglobulin fraction of plasma from persons vaccinated with vaccinia vaccine.  It is effective for treatment of eczema vaccinatum and certain cases of progressive vaccinia; it might be useful also in the treatment of ocular vaccinia resulting from inadvertent implantation.  However, vaccinia immunoglobulin is contraindicated for the treatment of vaccinial keratitis.  Vaccinia immunoglobulin is recommended for severe generalized vaccinia if the individual is extremely ill or has a serious underlying disease.  Vaccinia immunoglobulin provides no benefit in the treatment of post-vaccinial encephalitis and has no role in the treatment of smallpox.  The Centers for Disease Control and Prevention (CDC) (2001) states that current supplies of vaccinia immunoglobulin are limited, and its use should be reserved for treatment of vaccine complications with serious clinical manifestations.  According to the CDC (2001), vaccinia immunoglobulin should be administered as early as possible after the onset of symptoms.  Doses can be repeated, usually at intervals of 2 to 3 days, until recovery begins (e.g., no new lesions appear).  The CDC is currently the only source of vaccinia immunoglobulin for civilians.

Rabies Immune Globulin

Rabies immune globulin is indicated for treatment of rabies exposure where the animal has escaped or is known to be rabid at the time of direct exposure or attack.  Treatment of rabies exposure is comprised of a series of rabies vaccine (human diploid cell vaccine, HDCV) and a single rabies immune globulin injection (Rabies Immune Globulin, RIG).  For persons not previously vaccinated with HDCV, the usual frequency is a single IM injection of RIG and a series of HDCV consisting of 1-ml IM injection in the deltoid area on days 0, 3, 7, and 14.  For persons previously vaccinated with HDCV, 2 HDCV IM injections are given on days 0 and 3.  The literature indicates rabies immune globulin should not be administered to previously vaccinated individuals.

Gautret and colleagues (2018) stated that recent studies demonstrated that rabies post-exposure prophylaxis (RPEP) in international travelers is suboptimal, with only 5 to 20 % of travelers receiving rabies Ig (RIG) in the country of exposure when indicated.  These investigators hypothesized that travelers may not be receiving RIG appropriately, and practices may vary between countries; they described the characteristics of travelers who received RIG and/or RPEP during travel.  These researchers conducted a multi-center review of international travelers exposed to potentially rabid animals, collecting information on RPEP administration.  Travelers who started RPEP before (Group A) and at (Group B) presentation to a GeoSentinel clinic during September 2014 to July 2017 were included.  These investigators included 920 travelers who started RPEP.  Approximately 2/3 of Group A travelers with an indication for RIG did not receive it.  Travelers exposed in Indonesia were less likely to receive RIG in the country of exposure (RR: 0.30; 95 % CI: 0.12 to 0.73; p = 0.01).  Travelers exposed in Thailand (RR 1.38, 95% CI: 1.0 to 1.8; p = 0.02], Sri Lanka (RR 3.99, 95 % CI: 3.99 to 11.9; p = 0.013), and the Philippines (RR 19.95, 95 % CI: 2.5 to 157.2; p = 0.01), were more likely to receive RIG in the country of exposure.  The authors concluded that the findings of this analysis highlighted gaps in early delivery of RIG to travelers and identified specific countries where travelers may be more or less likely to receive RIG.  More detailed country-level information would help inform risk education of international travelers regarding appropriate rabies prevention.

Soentjens and associates (2021) noted that data on RPEP and the use of human rabies immunoglobulins (HRIG) in Belgium are scarce.  These researchers examined the timely administration of HRIG after rabies exposure.  The secondary objective was to evaluate the adequate antibody response following PEP.  They reviewed all medical records from July 2017 to June 2018 of patients seeking care at, or referred to, the Institute of Tropical Medicine and the University Hospital, Antwerp for the administration of HRIG following potential rabies exposure abroad or in Belgium.  A timely response was defined as starting HRIG with a delay of less than or equal to 48 hours and rabies vaccination in the first 7 days after exposure.  Adequate antibody response was defined as a titer of greater than 5.0 IU/ml in case of bat-related exposure and greater than 3.0 IU/ml in case of exposure to other animals.  Titers were measured 10 days after the last PEP vaccine dose, using the rapid fluorescent focus inhibition test (RFFIT).  Of the 92 cases treated with HRIG, 75 were evaluated.  The majority of injuries were acquired in Asia (n = 26, 34 %) and in Western Europe (n = 18, 24 %), of which 17 in Belgium.  The 5 most frequently recorded countries overseas were Indonesia (n = 13), Thailand (n = 7), Morocco (n = 4), Peru (n = 3) and Costa Rica (n = 3).  Administration of immunoglobulins was related to injuries by dogs (36 %), monkeys (25 %) or bats (22 %).  A timely response was observed in 16 (21, 33 %) and in 55 (73, 33 %) of subjects receiving HRIG (less than or equal to 48 hours) or rabies vaccine (less than 7days), respectively.  The mean time between exposure and the 1st administered dose of rabies vaccine and HRIG was 7.7 and 8.7 days, respectively.  The mean delay for HRIG administration was 9.6 days and 6 days for abroad and inland risks, respectively.  In 15 of 16 (94 %) bat-related cases the antibody titer after full PEP was greater than 5.0 IU/ml.  In 38 of 47 (81 %) cases related to other animals the RFFIT titer was greater than 3.0 IU/ml.  All low-responders received additional rabies injections.  The authors concluded that the findings of this study showed a substantial time delay between the animal-related risk and the administration of HRIG, in particular when the injury occurred abroad.  More targeted communication regarding the risks of rabies and preventable measures may reduce this delay.  Furthermore, the antibody response was inadequate in some cases following full PEP administration according to the Belgian recommendation.

Kessels and colleagues (2019) stated that rabies is a fatal zoonotic disease preventable through timely and adequate PEP to potentially exposed persons, i.e., wound washing and antisepsis, a series of intra-dermal (ID) or IM rabies vaccinations, and rabies immunoglobulin in WHO category III exposures.  The 2010 WHO position on rabies vaccines recommended PEP schedules requiring up to 5 clinic visits over the course of approximately 1 month.  Abridged schedules with less doses have potential to save costs, increase patient compliance, and thereby improve equitable access to life-saving PEP for at-risk populations.  These investigators systematically reviewed new evidence since that considered for the 2010 position paper to examine the following: immunogenicity and effectiveness of PEP schedules of reduced dose and duration; new evidence on effective PEP protocols for special populations; and the effect of changing routes of administration (ID or IM) during a single course of PEP.  The search identified a total of 14 relevant studies.  The identified studies supported a reduction in dose or duration of rabies PEP schedules.  The 1-week, 2-site ID PEP schedule was found to be most advantageous, as it was safe, immunogenic, supported by clinical outcome data and involved the least direct costs (i.e., cost of vaccine) compared to other schedules.  To supplement this evidence, as yet unpublished additional data were reviewed to support the strength of the recommendations. The authors concluded that available evidence suggested that changes in the rabies vaccine product and/or the route of administration during PEP is possible.  Moreover, these researchers noted that few studies have examined PEP schedules in persons with suspect or confirmed rabies exposures; gaps exist in understanding the safety and immunogenicity of novel PEP schedules in special populations such as infants and immunocompromised individuals.  They also noted that available data indicated that administering rabies vaccines during pregnancy is safe and effective.

Tetanus Immune Globulin

Intramuscular injection of tetanus immune gamma globulin are indicated for prevention of tetanus in immunized or non-immunized persons for neglected or tetanus-prone wounds (contaminated, necrotizing, or puncture wounds).  Post-exposure prophylaxis with tetanus toxoid is recommended under accepted guidelines for wounded persons who have not completed the 3-dose primary vaccination series, and those who have completed vaccination more than 10 years ago.  In addition, accepted guidelines state incompletely vaccinated persons with serious or contaminated wounds should receive human tetanus immune globulin.  The usual dose is a single IM injection repeated at 4-week intervals, if necessary.

Rubeola (Measles) Immune Globulin

Intramuscular injection of measles (rubeola) immune globulin is indicated for unvaccinated individuals exposed to the disease.  Accepted guidelines recommend that the immune globulin should be administered within 6 days of exposure.

Tunis and colleagues (2018) stated that human Ig products are currently recommended as PEP for measles in certain susceptible groups.  However, successful measles vaccination programs in North America have led to low circulation of measles virus and most blood donors now have vaccine-derived immunity.  Concurrently, the concentrations of anti-measles antibodies in human Ig products have shown trends of gradual decline and previously recommended doses and routes of administration may no longer be optimally protective.  These investigators reviewed the literature and updated recommendations on PEP for measles, including dosing and route of administration, for measles Ig PEP in susceptible infants and in individuals who are immuno-compromised or pregnant, in order to prevent severe disease.  The National Advisory Committee on Immunization (NACI) Measles, Mumps, Rubella, Varicella Working Group reviewed key literature, international practices, and product information for current Ig products pertaining to the optimal dosage and routes of Ig administration for measles PEP.  It then proposed evidence-based changes to the PEP recommendations that were considered and approved by NACI.  NACI continues to recommend that susceptible immuno-competent individuals 6 months of age and older, who are exposed to measles and who have no contraindications be given measles-mumps-rubella (MMR) vaccine within 72 hours of the exposure.  NACI recommends that for susceptible infants younger than 6 months of age, if injection volume is not a major concern, intramuscular Ig (IMIg) should be provided at a concentration of 0.5 ml/kg, to a maximum dose of 15 ml administered over multiple injection sites.  Susceptible infants 6 to 12 months old who are identified after 72 hours and within 6 days of measles exposure should receive IMIg (0.5 ml/kg) if injection volume is not a major concern.  For susceptible contacts who are pregnant or immuno-compromised, if injection volume is not a concern, IMIg can be provided at a concentration of 0.5 ml/kg understanding that recipients 30 kg or more will not receive the measles antibody concentrations that are considered to be fully protective.  Alternatively, in cases where injection volume is a major concern or for recipients 30 kg or more, intravenous immunoglobulin (IVIG) can be provided at a dose of 400 mg/kg.  NACI does not recommend that susceptible immuno-competent individuals older than 12 months of age receive Ig PEP for measles exposure due to the low risk of disease complications and the practical challenges of administration for case and contact management.  The authors concluded that NACI has updated the recommendations for measles PEP to reflect current evidence and best practices in order to prevent severe disease in Canada.  Consistent with recommendations in other countries, this includes consideration of off-label use of IVIG in some instances.

Matysiak-Klose and associates (2018) noted that passive immunization with Igs as PEP following contact with measles is recommended by the German Standing Committee on Vaccination (STIKO) especially for un-protected individuals at high risk of complications for whom active immunization is contraindicated, such as infants of less than 6 months of age, immuno-compromised patients and pregnant women.  The efficacy of passive immunization in preventing measles depends on how soon following exposure it is administered, the concentration of measles antibodies in the Ig products and dosage.  Since the global introduction of standard active immunization against measles and the concomitant reduction in virus circulation, the levels of measles virus (MV)-specific IgG antibodies in the population have dropped.  Thus, the concentration of MV-specific antibodies in Ig products derived from human plasma donors has declined as the proportion of vaccinated donors has increased.  The MV-neutralizing capacity of Ig products is not routinely tested in Germany.  No official data exist on the concentrations of MV-specific IgG antibodies in individual batches of Igs available in Germany and the required minimum level for MV-specific IgG is not stipulated.  The STIKO re-evaluated available data and measurements of MV-neutralizing capacities of available Ig products in Germany at the National Reference Centre Measles, Mumps, Rubella at the Robert Koch Institute.  Based on the findings, STIKO modified its previous recommendations on the post-exposure use of Igs (2001), especially with respect to risk groups, application and dosage.  STIKO now recommends a single IV administration of Igs (400 mg/kg body weight) as soon as possible, preferably within 6 days, following exposure to measles, specifically for infants aged less than 6 months, susceptible pregnant women and immuno-compromised patients.

Immune Globulin for Rubella (German Measles)

The use of immune globulin for pregnant women with acute infection is controversial.  There are no data to suggest that immune globulin will have any beneficial effect on the fetal response to disease.  Thus, the CDC recommends limiting the use of immune globulin to women with known rubella exposure who decline pregnancy termination.  The usual dose of immune globulin is a single IM injection.

Infantile Botulism Immune Globulin

Arnon et al (2006) created the orphan drug Human Botulism Immune Globulin Intravenous (Human) (BIG-IV), which neutralizes botulinum toxin, and evaluated its safety and efficacy in treating infant botulism, the intestinal-toxemia form of human botulism.  These investigators performed a 5-year, randomized, double-blind, placebo-controlled trial statewide, in California, of BIG-IV in 122 infants with suspected (and subsequently laboratory-confirmed) infant botulism (75 caused by type A Clostridium botulinum toxin, and 47 by type B toxin); treatment was given within 3 days after hospital admission.  These researchers subsequently performed a 6-year nationwide, open-label study of 382 laboratory-confirmed cases of infant botulism treated within 18 days after hospital admission.  As compared with the control group in the randomized trial, infants treated with BIG-IV had a reduction in the mean length of the hospital stay, the primary efficacy outcome measure, from 5.7 weeks to 2.6 weeks (p < 0.001).  BIG-IV treatment also reduced the mean duration of intensive care by 3.2 weeks (p < 0.001), the mean duration of mechanical ventilation by 2.6 weeks (p = 0.01), the mean duration of tube or intravenous feeding by 6.4 weeks (p < 0.001), and the mean hospital charges per patient by 88,600 dollars (in 2004 U.S. dollars; p < 0.001).  There were no serious adverse events attributable to BIG-IV.  In the open-label study, infants treated with BIG-IV within 7 days of admission had a mean length of hospital stay of 2.2 weeks, and early treatment with BIG-IV shortened the mean length of stay significantly more than did later treatment.  The authors concluded that prompt treatment of infant botulism type A or type B with BIG-IV was safe and effective in shortening the length and cost of the hospital stay and the severity of illness.

Underwood et al (2007) reported a tertiary care hospital's 30-year experience with the diagnosis, treatment, and outcome of infant botulism in the PICU before and after the availability of Botulism Immune Globulin Intravenous.  This was a retrospective medical chart review of the 67 patients who had received a diagnosis of infant botulism and were admitted to the ICU from 1976 to 2005.  The ages on presentation, length of hospital stay, length of ICU stay, length of mechanical ventilation, and type of botulism toxin were recorded and compared for patients who had received Botulism Immune Globulin Intravenous and those who had not.  On the basis of these results, conclusions were drawn regarding the effect of Botulism Immune Globulin Intravenous on the morbidity of infant botulism.  A total of 67 patients' charts were reviewed; 23 male and 29 female patients did not receive Botulism Immune Globulin Intravenous.  Of patients who did not receive Botulism Immune Globulin Intravenous, the median age at presentation was 71 days, median length of hospital stay was 35 days, ICU stay was 24 days, and duration of mechanical ventilation was 17 days.  A total of 40 % had type A toxin, and 60 % had type B toxin.  There was a significant difference between patients with toxin types A and B in length of hospital stay but not length of ICU stay or mechanical ventilation.  Patients with type A toxin were significantly older than patients with type B toxin.  Fifteen children received Botulism Immune Globulin Intravenous.  There were statistically significant differences in length of hospital stay, length of ICU stay, and length of mechanical ventilation between patients who received Botulism Immune Globulin Intravenous and those who did not.  The authors concluded that the use of Botulism Immune Globulin Intravenous significantly decreased the length of ICU stay, length of mechanical ventilation, and overall hospital stay in children with infant botulism.

Vanella de Cuetos et al (2011) stated that infant botulism is the most common form of human botulism in Argentina and the United States.  BabyBIG (botulism immune globulin intravenous [human]) is the antitoxin of choice for specific treatment of infant botulism in the United States.  However, its high cost limits its use in many countries.  These investigators reported the effectiveness and safety of equine botulinum antitoxin (EqBA) as an alternative treatment.  They conducted an analytical, observational, retrospective, and longitudinal study on cases of infant botulism registered in Mendoza, Argentina, from 1993 to 2007.  They analyzed 92 medical records of laboratory-confirmed cases and evaluated the safety and efficacy of treatment with EqBA.  Forty-nine laboratory-confirmed cases of infant botulism demanding admission in ICUs and mechanical ventilation included 31 treated with EqBA within the 5 days after the onset of signs and 18 untreated with EqBA.  EqBA-treated patients had a reduction in the mean length of hospital stay of 23.9 days (p = 0.0007).  For infants treated with EqBA, the ICU stay was shortened by 11.2 days (p = 0.0036), mechanical ventilation was reduced by 11.1 days (p = 0.0155), and tube feeding was reduced by 24.4 days (p = 0.0001).  The incidence of sepsis in EqBA-treated patients was 47.3 % lower (p = 0.0017) than in the untreated ones.  Neither sequelae nor adverse effects attributable to EqBA were noticed, except for 1 infant who developed a transient erythematous rash.  The authors concluded that these results suggested that prompt treatment of infant botulism with EqBA is safe and effective and that EqBA could be considered an alternative specific treatment for infant botulism when BabyBIG is not available.

Also, an UpToDate review on “Botulism” (Pegram, 2023) states that "Infant botulism is treated with human-derived intravenous botulism immune globulin (called BIG-IV or BabyBIG). BIG-IV should be administered as early as possible in the illness".

BabyBIG, botulism immune globulin intravenous (human) (BIG-IV), is an orphan drug that consists of human-derived botulism antitoxin antibodies that is approved by the FDA for the treatment of infant botulism types A and B.

BabyBIG is given as a single IV infusion.  Recommended dose is 1.5 ml/kg (75 mg/kg) given as a single intravenous infusion.  Begin infusion slowly (0.5 ml/kg/h); if no untoward reaction in 15 minutes, increase rate to 1.0 ml/kg/h (2.2, 2.3).  (At the recommended rates, infusion of the indicated dose should take 97.5 mins total elapsed time).  

Plasma-Derived Immunoglobulin for COVID-19

Volk et al (2022) noted that patients with primary or secondary immunodeficiency (PID or SID) face increased insecurity and discomfort in the light of the COVID-19 pandemic, not knowing if and to what extent their co-morbidities may impact the course of a potential SARS-CoV-2 infection.  In addition, recently available vaccination options might not be amenable or effective for all patients in this heterogeneous population; thus, these patients often rely on passive immunization with plasma-derived, intravenous or subcutaneous immunoglobulin (IVIG/SCIG).  Whether the ongoing COVID-19 pandemic and/or the progress in vaccination programs would lead to increased and potentially protective titers in plasma-derived immunoglobulins (Ig) indicated (e.g., for humoral immunodeficiency) remains a pressing question for this patient population.  These investigators examined SARS-CoV-2 reactivity of U.S. plasma-derived IVIG/SCIG products from the end of 2020 until June 2021 as well as in convalescent plasma (CP) from May 2020 to August 2020 to determine if potentially neutralizing antibody titers may be present.  Final containers of IVIG/SCIG and CP donations were analyzed by commercial ELISA for anti-SARS-CoV-2 S1-receptor binding domain (RBD) IgG as well as micro-neutralization assay using a patient-derived SARS-CoV-2 (D614G) isolate.  Neutralization capacities of 313 single plasma donations and 119 plasma-derived IVIG/SCIG lots were determined.  Results obtained from both analytical methods were normalized against the WHO International Standard.  Finally, based on dense pharmacokinetic profiles of an IVIG preparation from previously published investigations, possible steady-state plasma levels of SARS-CoV-2 neutralization capacities were approximated based on currently measured anti-SARS-CoV-2 potencies in IVIG/SCIG preparations.  CP donations presented with high variability with regards to anti-SARS-CoV-2 reactivity in ELISA as well as in neutralization testing.  While approximately 50 % of convalescent donations were not/low neutralizing, approximately 10 % were at or above 600 IU/ml.  IVIG/SCIG lots derived from pre-pandemic plasma donations did not show neutralizing capacities for SARS-CoV-2.  Lots produced between December 2020 and June 2021 entailing plasma donations after the emergence of SARS-CoV-2 showed a rapid and constant increase in anti-SARS-CoV-2 reactivity and neutralization capacity over time.  While lot-to-lot variability was substantial, neutralization capacity increased from a mean of 21 IU/ml in December 2020 to 506 IU/ml in June 2021 with a maximum of 864 IU/ml for the most recent lots.  Pharmacokinetic extrapolations, based on non-compartmental superposition principles using steady-state reference profiles from previously published pharmacokinetic investigations on IVIG in PID, yielded potential steady-state trough plasma levels of 16 IU/ml of neutralizing SARS-CoV-2 IgG based on the average final container concentration from May 2021 of 216 IU/ml.  Maximum extrapolated trough levels could reach 64 IU/ml based on the latest maximal final container potency tested in June 2021.  The authors concluded that SARS-CoV-2 reactivity and neutralization capacity in IVIG/SCIG produced from U.S. plasma rapidly and in part exponentially increased in the 1st half of 2021.  The observed increase of final container potencies is likely trailing the serological status of the U.S. donor population in terms of COVID-19 convalescence and vaccination by at least 5 months due to production lead times and should in principle continue at least until Fall 2021.  These researchers stated that the data support rapidly increasing levels of anti-SARS-CoV-2 antibodies in IVIG/SCIG products, implicating that a certain level of protection could be possible against COVID-19 for regularly substituted PID/SID patients; however, more research is still needed to confirm which plasma levels are needed to provide protection against SARS-CoV-2 infection in immune-compromised patients.

Clinical Management of Monkeypox

Webb et al (2022) noted that monkeypox (MPX) is an important human orthopoxvirus infection.  There has been an increase in MPX cases and outbreaks in endemic and non-endemic regions in recent decades.  In a systematic review, these investigators examined the availability, scope, quality and inclusivity of clinical management guidelines for MPX globally.  They searched 6 databases from inception until October 14, 2021, augmented by a grey literature search until May 17, 2022.  MPX guidelines providing treatment and supportive care recommendations were included, with no exclusions for language; 2 reviewers assessed the guidelines.  Quality was assessed using the Appraisal of Guidelines for Research and Evaluation II tool.  Of 2,026 records screened, 14 guidelines were included.  Overall, most guidelines were of low-quality with a median score of 2 out of 7 (range of 1 to 7), lacked detail and covered a narrow range of topics.  Most guidelines focused on adults, 5 (36 %) provided some advice for children, 3 (21 %) for pregnant women, and 3 (21 %) for people living with HIV.  Treatment guidance was mostly limited to advice on anti-viral; 7 guidelines advised cidofovir (4r specified for severe MPX only); 29 % (4/14) tecovirimat, and 7 % (1/14) brincidofovir.  Only 1 guideline provided recommendations on supportive care and treatment of complications.  All guidelines recommended vaccination as post-exposure prophylaxis (PEP); 3 guidelines advised on vaccinia immune globulin as PEP for severe cases in individuals with immunosuppression.  The authors concluded that the findings of this systematic review highlighted a lack of evidence-based clinical management guidelines for MPX globally.  There is a clear and urgent need for research into treatment and prophylaxis including for different risk populations.  The current outbreak provided an opportunity to accelerate this research via coordinated high-quality studies.  New evidence should be incorporated into globally accessible guidelines, to benefit patient and epidemic outcomes.  A “living guideline” framework was recommended to improve availability of up-to-date clinical management guidelines, developed using robust methodologies and inclusive of different at-risk populations.  These researchers stated that urgent investments into research to identify optimal treatment and prophylaxis strategies are needed for the whole population, in any setting, to benefit patient care and outcomes.

Kang et al (2023) stated that in addition to the COVID-19 waves, the world faced a global MPX outbreak.  As the daily confirmed cases of MPX infection across epidemic and non-epidemic countries are increasing, taking measures to control global pandemic remains crucial.  In a comprehensive overview, these investigators provided fundamental knowledge for the prevention and control of future outbreaks of this emerging epidemic.  The review was carried out using PubMed and Google Scholar databases; the search terms used were "monkeypox", "MPX tropism", "replication signaling of MPX", "biology and pathogenicity of MPX", "diagnosis of MPX", "treatment of MPX", and "prevention of MPX" etc.  The update epidemic data were collected from the websites of the World Health Organization (WHO), CDC, and Africa Center for Disease Control and Prevention (ADCC).  High-quality research results published in authoritative journals were summarized and cited.  Excluding all duplicates, non-English published references, and irrelevant literature, a total of 1,436 studies were assessed for eligibility.  It is still difficult to diagnose MPX simply based on clinical manifestations; thus, employing polymerase chain reaction (PCR) technology to provide confirmed evidence for the diagnosis of MPX appeared to be the preferred and indispensable strategy.  The therapeutic approach for MPX infection is mainly symptomatic and supportive; anti-smallpox virus drugs including tecovirimat, cidofovir, and brincidofovir can be employed in severe cases.  Timely identification and isolation of confirmed cases, cutting off dissemination routes, and vaccination of close contacts are effective measures to control MPX.  Furthermore, smallpox vaccines (JYNNEOS, LC16m8, and ACAM2000) can be under consideration due to their immunological cross-protection among Orthopoxvirus.  Nevertheless, given the low quality and scarcity of relevant evidence of current anti-viral drugs and vaccines, deeply seeking for the MAPK/ERK, PAK-1, PI3K/Akt signaling, and other pathways involved in MPX invasion may provide potential targets for the treatment, prevention, and control of the epidemic.  The authors concluded that in response to the current MPX epidemic, the development of vaccines and anti-viral drugs against MPX, as well as the rapid and precise diagnostic methods are still urgently needed.  Sound monitoring and detection systems should be established to limit the rapid spread of MPX worldwide.  Moreover, these researchers noted that vaccinia immune globulin intravenous (VIGIV) VIGIV is a specific antibody produced by individuals who have been vaccinated against smallpox, and it is approved by the FDA for the treatment of complications arising from VACV vaccination, including progressive vaccinia, severe generalized vaccinia, eczema vaccinatum, and vaccinia infections in individuals with skin conditions and aberrant infections induced by VACV (except in cases of isolated keratitis).  However, there are no data on the effectiveness of its use in the treatment of MPX infection, and it remains unclear whether severe cases of MPX would benefit from it.

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References