Published in :Northern Medical Journal, 2003
LEVAMISOLE IN THE PREVENTION OF RECURRENT INFECTIONS PARTICULARLY IN CHILDREN - A CASE SERIES
Dr. Md. Mujibur Rahman
Summary: Levamisole, a synthetic imidazothiazole derivative, which had been originally designed for anthelmintic properties, have immuno-stimulatory properties in vivo. Clinical use of the drug as an immunotropic agent has been applied commonly, as adjuvant therapy in colon cancer and prevention of serious bacterial infection in children with nephrotic syndrome [7,8.10,11,16]. In this study immunotropic activity of levamisole has been utilized on trial basis for the benefit of the children suffering from recurrent acute infective diseases e.g. recurrent acute respiratory tract infection, recurrent sore throat with tonsillitis, CSOM, recurrent herpes infection, sinusitis etc. Several immuno-deficient cases of children from the district of Rangpur of Bangladesh, diagnosed only on clinical basis due to suffering particularly from repeated acute respiratory tract infections, recurrent herpes infection, chronic autitis media and recurrent tonsillitis, were treated with levamisole in a different dose than as anthelmintic. Excellent and almost permanent cure was observed without any side effects over the next eight to thirteen years of follow up in 30 cases (at the time of writing this manuscript). Only 9 types of recurrent infections are mentioned below. In almost all cases the history of recurrence of the particular disease was more than one year and in some cases it was 5 to 20 years. These periods of recurrent infections before the treatment with levamisole were considered as control period.
Levamisole, a three-ringed anthelmintic drug, has good immunotropic activity as well as to some extent antiviral properties . The drug has very little side effects. It has been used successfully in the treatment of Herpes progenitalis. It is observed that immunotropic activity of levamisole is due to the stimulation of active immunity, and the action appears to be due to enhancement of phagocytes and direct action on earlier stages of T- cell function, augmenting helper, amplifier, cytotoxic, and suppressor T- cell functions [1,2,3]. Patients with impaired delayed hypersensitivity show restoration of skin reactivity after levamisole therapy. It has been used in immunodefficiency states, aphthous stomatatis, autoimmune diseases (Rheumatoid arthritis, SLE) and in malignant diseases e.g. carcinoma of colon [7,8,11]. Levamisole augments nonspecific inflammation by increasing chemotaxis of PMN leucocytes and monocytes and increasing phagocytosis . These effects can be dramatic when these functions are impaired, but little effects on normal responses.
Levamisole has been used in the treatment of chronic thrombocytopenic purpura  Congenital immuno-deficiency is not a common disease but the condition is not rare in the children which have been delivered prematurely and may also occur rarely in some of them which have delivered after full-term. In a developing country like Bangladesh, still, it is not easy to confirm a case to be immuno-deficient because it requires sophisticated laboratory tests. But, clinically one can doubt of a child who suffers repeatedly from infective diseases particularly acute respiratory tract infections almost continuously with febrile illnesses in a community or in a group of families where other children differ conspicuously. In this way, different types of cases of immuno-deficient state were treated with levamisole successfully preventing the recurrence of the infections.
In the month of December 1987, a mother came with her baby of age 6 months with history of repeated attacks of acute respiratory tract infections. The child was her first issue and was a premature baby, delivered in 33 weeks of pregnancy. She gave history of using 3 or 4 course antibiotics (amoxycillin and cephlexin) in a month since the birth of the child. Routine blood count showed leucocytosis due to neutrophilia (Total count 11500; neutrophil-76%, lymphocyte-21%, monocyte-2%, Eos-1%). With the permission of the parents and explaining the nature of the drug, levamisole was prescribed after 7 days course of amoxycillin (it was given many times before). The dose of levamisole was different than that as anthelmintic. Here, initially the dose was 20mg levamisole twice daily for 4 days. After 7 days of interval, the drug was given for 3 days with the same dose. Again, after 15 days of interval 3 days of treatment of the same dose was given. Then after an interval of one month and three months interval 2 courses of 3 days treatment were given. Patient was being observed closely during this period and found dramatically responding to the drug. The child had no ARI on the following year and even during this period the child needed no antibiotics at all. During follow-up the patient is now 16 years of age. Six months ago the patient complained recurrent upper respiratory infections particularly chronic sinusitis for the last two years for which she had to consult with ENT specialists frequently. Again with the permission of her parents she was given levamisole 40mg twice for three consecutive days and another dose of three days treatment after an interval of 15 days. For the last 4 months she is all right and she needed no visit to ENT specialist now.
In February 1993, a father reported that his daughter of age 14 months was being suffering from repeated attack of fever with cough from 6 months of her birth. She always needed antibiotics usually 2 to 3 times in a month prescribed by several pediatricians. This child was delivered normally after full term of pregnancy. The parents were hopeless about their daughter. The child was undergone routine investigation of blood (CBC), urine and stool during attack. Reports showed nothing contributory than acute infection. After explaining the nature of the drug (levamisole) to the father and with his consent levamisole was given in a dose of 25mg twice daily for 4 days and repeated the drug in the same way as the first case. The patient responded dramatically to the drug. Since the treatment the child was all right and only she developed transient febrile illness at the age of 4 years and treated with paracetamol only and a boosting dose of levamisole for 3 days. The child is 8 years and 6 months of age and is all right now.
In 1989 a girl of 19 years was suffering from repeated sore throat with tonsillitis for the last few years and treated by different ENT specialist and ultimately was advised for tonsillectomy. Levamisole was given 60mg twice daily for 4 days and repeat the dose in the same pattern as before. The lady responded well to the drug without any side effects. She did not need for surgery and suffers rarely from sore throat on follow up of 10 years. She is mother of two sons now.
In December 1993, a father came with his child of age about one and half year with history of repeated attack with upper respiratory tract infection and febrile illness for the last one year. During every attack the child did not cured unless she was given a course of antibiotic. After routine investigation of blood, levamisole was administered in immunotropic dose. After the treatment the child became all right within one month. Till then she rarely suffers from sore throat. At the age of 9 and half years the child developed sudden rise of temperature (40oC). On examination only her tonsil was found enlarged moderately. Clinically though it appeared to be viral in origin, levamisole was given along with a course of amoxycillin. The temperature subsided in 24 hours and the child attended to school in two days.
This case was not a of respiratory tract infection but presented with pyogenic extensive skin infection for the last 6 months. The patient was female child of about 8 and half years of age in February 1998. The father of the patient is an ophthalmologist who had taken many measures including treatment from dermatologist, pediatrician and also homeopathic measure for the cure of his daughter and failed. Ultimately he decided to go to the referral hospital in capital City for the treatment of his daughter. Incidentally the father of the patient was informed about the cure of several patients with levamisole therapy. When he agreed, levamisole was given in a dose of 40 mg twice daily for 4 days and repeated the drug after an interval of a week, a fortnight and a month accordingly. After one month he reported more than 80% cure of her daughter. However the child was completely cured in one and half month of starting the treatment she was given another dose of levamisole after an interval of 3 months. Since the treatment more than five years have passed the child did not suffered from any of this type of diseases.
A girl of age 13 years in 1999, presented with sore throat, chronic tonsillitis and maxillary sinusitis (X-ray PNS report), was advised for tonsillectomy by ENT specialist. Explaining the nature of the drug to the parents, levamisole was prescribed to the girl in immunotropic dose. After 3 months of the completion of the treatment patient attended another ENT specialist who examined and investigated her and commented that she has no ENT problem. It is now three and half year passed after the levamisole, only once (one year after treatment) she suffered from upper respiratory tract infection, which needed a course of doxycycline for treatment.
Chronic autitis media is actually a problem in children who once suffered from it, due to its recurrence, each time when the patient develop an upper respiratory tract infection. In December, 2000, two cases of chronic autitis media with purulent discharges from ears- one of age 1 year and another 2 and half years, had been suffering for last six months. These patients were given antimicrobials several times to cure temporarily. When these children were treated with levamisole they were cured fully and all right for the last one and half years of follow up. Another child of 4 years of age was suffering from CSOM with recurrent purulent discharge from her right ear. There was perforation on her eardrum. She was given levamisole. Initially she responded well and until 6 months there was no complain but after that she developed the symptom of discharge once. Again she was treated with levamisole and 1 year passed there is no report of purulent discharge.
Infection by Herpes Simplex Virus (HSV) types I and II represent a worldwide medical problem. After the primary infection the virus establishes a life-long latency in the dorsal root ganglia and recurrences may occur at unpredictable times and rate. The most frequent clinical presentation of HSV infection is recurrent herpes labialis and herpes genitalis. In January 2001 a shopkeeper of 26 years complained of his recurrent swelling of his both lips with blebs at least three times a year with fever for the last five years. Each time he got symptomatic treatment but after two weeks he would cure automatically but got no permanent cure. Explaining the nature of the drug, levamisole was prescribed. After two years passed, on follow up the patient did not give history of recurrence of herpes labialis.
Case group 9
Aphthous ulcer is not an uncommon disease. Recurrence of the disease is very problematic to the patient suffering from the disease. Three cases were treated successfully without recurrence. Two girls of age 15 and 16 years respectively complained repeated extensive ulceration in the mouth and throat. They were investigated for blood for CBC, routine examination of urine and stool. Their total WBC count were 8,000 and 8500 per micro liter, differential count was within normal range. Third one was a elderly female of 50 years, who was suffering from aphthous ulcer for the last 10 years. She was suffering from joint pain. Her total count of blood was slight, (11,700/cumm), polymorph 75%. All the three patients were treated with levamisole therapy. It is about one year passed of follow-up, there was no report of recurrence of oral ulcer.
Levamisole as an immunopotentiating drug is familiar for long time. Its exact mechanism, although was not clear before, now appears to be clearly evident. Now levamisole is considered one of the six drugs that are approved by FDA to be used as immunotherapy . As an adjuvant, the drug is used as adjuvant in the treatment of colon cancer [8, 10, 11] but for the prevention recurrent infection use of it is not yet documented. Finding no alternative to help the above cases of recurrent infections, levamisole was applied in minimum dose to them. The first case was a premature baby and passive immunity from maternal side should be deficient. So this child suffered a lot since her birth. After levamisole therapy her immunodeficiency was minimized and susceptibility to repeated infection was abolished. The second case was different from the first one. This child was a full term baby. So during the first 6 months of her birth she was almost all right. She might have some immunodeficiency due to genitical cause. So after 6 months of her birth she gradually became prone to infections. When levamisole therapy was administered her immunodeficiency was corrected and she got relief from the symptoms. The third and fourth cases were neglected because their infections were mostly limited to upper respiratory tract. It might be due to that their immunodeficiency was of low-grade type. However the fourth case had escaped from surgical intervention after levamisole therapy. The Fifth case was different from the other cases. This case was mostly susceptible to frequent skin infections. As the infections were refractory to other treatment, the father of the patient, who is a doctor himself agreed to treat her daughter with levamisole. Cure of the patient with levamisole therapy proved that this girl also might suffer from immunodeficiency whatever its grade was. In autitis media, if perforation persist it may be difficult to treat with levamisole alone. When perforation gets healed, then recurrence is not expected. In our country recurrent oro-labial herpes simplex virus infection (HSV) is very common. The clinical expression varies according to the body site, the infected cell type, the relationship between HSV and the host immune status. For any cause, when the immune status of a previously infected person with HSV goes down, recurrence is common. Levamisole can correct this immunodeficiency and thus prevent the recurrence [4,5,6].
Use of levamisole in the treatment of aphthous ulcer is not new . Excellent responses observed during the treatment of aphthous ulcer in this dose schedule of levamisole.
CONCLUSIONS: Immuno-deficient patient is always vulnerable to repeated infections. So, mortality and morbidity is higher among the immuno-deficient children due to infectious disease particularly acute respiratory tract infections. Management of these cases is not an easy task. But when cases of repeated acute respiratory tract infections and other infections, clinically suspected to be due to immuno- deficiency, are treated with levamisole therapy, mortality and morbidity can be minimized to much extend. Other than ARI cases, many of the infectious cases can also be managed by levamisole therapy in immuno-deficient group of patient. Many patients, those are not mentioned in the case series, a borderline state had been also treated with levamisole with good outcome but no side effects except one case, which showed mild temporary passage of mucous in the stool. Two cases of same family became slight irritating temporarily for few weeks after treatment. Otherwise, no significant side effects were noticed in almost all of the cases during the immuno-therapy with levamisole. However, before any firm conclusion, much clinical trials should be undertaken with levamisole therapy, along with laboratory proof for better acceptance of the method of the treatment. Wide publication of this method of treatment should decrease morbidity and mortality particularly among the pediatric group in a significant level. Definite immuno-deficiency cases whether congenital or acquired and in resistant cases of tuberculosis, in opportunistic infection like cryptococcosis, histoplasmosis, and candidiasis etc. levamisole might be employed as adjuvant therapy. Even it will be not unwise, to propose to treat the cases of AIDS with levamisole therapy as adjuvant along with other therapy.
 Laurence DR, Barnett PN, Brown MJ. Neoplastic disease and immunosupression In Clinical Pharmacology, 8th edition. Churchill Livingstone- Newyork, 1997; page 560.
 Bondy DC, Bondy PK, Feinstein AR.et al editors. Antivirus drug. In the Merck Manual of Diagnosis and therapy; 14th edition, Merck &Co., Inc.N.J. 1982; Page 23-24.
 Katzung BG, editor. Basic and Clinical Pharmacology. Published by Prentice-Hall International Inc. 6th edition, 1995; page 550-551.
 Jarratt M. Herpes simplex infection. Arch. Dermatol. 1983, 119, 99-103.
 Pereira FA. Herpes simplex, Evolving concepts. J. Am. Acad. Dermatol. 1996, 35, 503-520.
 Whitley RJ. Herpes Simplex Virus Infections. In, Herpesvirus Infections. Eds, Glaser R, Jones JF. P1-58. Marcel Dekker, New York, 1994.
 Haskell CM, ed. Cancer treatment, 3rd ed. Philadelphia: WB Saunders Co, 1990:943-4.
 Krogh CME, ed. Compendium of pharmaceuticals and specialties, 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993:428-9.
 Kouassi E, Caille G, Lery L, et al. Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine. Biopharm Drug Disp 1986;7:71.
 Mutch RS, Hutson PR. Levamisole in the adjuvant treatment of colon cancer. Clin Pharm 1991;10:95-109.
 Stevenson HC, et al. Review article: Levamisole: Known effects on the immune system, clinical results and future applications in the treatment of cancer. J Clin Oncol 1991;9(11):2052-66.
 Rebora A, Dallegri F, Patrone F. Neutrophil dysfunction and repeated infections: influence of levamisole and ascorbic acid. Br J Dermatol 1980 Jan;102(1):49-56
 Zhong Guo Zhong Xi Yi Jie He Za Zhi. The Treatment of 42 Cases of Chronic Thrombocytopenic Purpura with Integrated Chinese-Western Medicine. Chinese National Journal of Integrated Chinese-Western Medicine), 1994, #8, p. 495-496.
 www.Immunopharmacology page 8.htm.
 Jude Rochette. Treating infammmed mouth. www.WSAVA 2001- Treating the Infammed mouth.htm.
 P McINTYRE & JC CRAIG. Prevention of serious bacterial infection in children with nephrotic syndrome. Journal of Paediatrics and Child Health. Volume 34 Issue 4 Page 314 - August 1998 doi:10.1046/j.1440-1754.1998.00232.x.