From the study of 296 cases of Bancroftian filariasis treated with Hetrazan in British Guiana the following conclusions and recommendations for treatment seem to be justified:
1.Rapid reductions in microfilariae are obtained when oral doses of from 0.2 to 2.0 mg. per kg. of Hetrazan are given three times daily. Most cases treated with 0.4 mg. per kg. or higher show negative counts 1 week after treatment has started, and these negative counts have been maintained generally for as long as follow-up examinations have been made (up to 4 months after cessation of treatment). Following doses approximating 0.2 mg. per kg. three times daily for 21 days or longer, the microfilariae may recur in small numbers at varying times after treatment has been stopped. This rarely occurs when higher doses are used. Very few cases are resistant to treatment.
2.The failure of microfilariae to recur in the peripheral blood after treatment has stopped in most cases indicates that the adult worms are dead or have been sterilized. It seems more likely that the adults are dead, since clinical improvement was obtained following acute exacerbations of filarial symptoms which we consider of allergic origin, and which are probably produced when filarial protein is released by dead worms.
3.Systemic reactions to Hetrazan itself are very mild and of short duration. Cases not sensitized to filarial protein rarely exhibit reactions of any sort during treatment. Headache, nausea, sedation, and malaise are probably side effects produced by Hetrazan itself, but these symptoms have never been severe nor long lasting.
4.Systemic reactions in clinical cases of filariasis during treatment with Hetrazan, particularly in cases with a history of severe filarial attacks, resemble filarial symptoms which occur in untreated patients. Nodular swellings, lymphangitis, pain in the abdominal region, temporary swellings of the extremities, and temporary aggravation of existing swellings, accompanied by fever and pain, occur with varying degrees of severity in clinical cases during treatment. Single or multiple manifestations occur at various periods after treatment is initiated. These have never reached alarming proportions, however, and in but extremely few cases has it been necessary to temporarily discontinue treatment or hospitalize patients because of reactions. In the few cases which were hospitalized, treatment was continued. It is difficult to explain these reactions in any way other than acute allergic phenomena brought about by the release of filarial protein in sensitized individuals. The total amount of protein released seems not as important as the relationship between the amount of antigen and the degree of sensitization of the individual. It appears obvious that even in non-sensitized individuals when the amount of foreign protein increases constantly, the time is reached when the tolerated amount is exceeded, and allergic reactions occur. On the other hand, in a highly sensitized individual, the amount of protein released from a single adult worm could produce a severe reaction.
The explanation of systemic reactions which sometimes occur during the treatment of this infection with Hetrazan on an allergic basis is further strengthened by the following facts:
(a)Patients infected with intestinal round worms or with no helminth infections whatever have never shown reactions other than those mentioned in item 3.
(b)Patients infected only with Acanthocheilonema perstans or Mansonella ozzardi, neither of which are affected by Hetrazan in doses effective against W. bancrofti, have shown no systemic reactions, even after prolonged courses of treatment.
(c)Patients infected with Onchocerca volvulus show systemic manifestations different in character and location from those occurring in W. bancrofti, suggesting that the site of the worms within the host governs the type and site of local reactions.
Despite the fact that symptoms during treatment have never reached alarming proportions, the possibility of severe allergic reactions should not be overlooked. It would probably be well to start treatment with low doses (0.2 to 0.5 mg. per kg.) in hypersensitized individuals with a history of unusually severe filarial attacks, although, as shown in the Kwakwani group, systemic reactions may occur during treatment with this dosage range. The possibility of alleviating the severity of some reactions by the use of anti-allergic medication should be considered.
5.The duration of dosage with Hetrazan in clinical cases cannot be based upon the rate of disappearance of microfilariae, because the dosage thus calculated may be sufficient to destroy microfilariae and the adult worms which produced them, but insufficient to kill worms which are screened by inflammed tissues and do not release microfilariae into the general circulation. Moreover, the duration of treatment cannot be determined by the complete disappearance of microfilariae from the blood stream, since it is believed that the effects produced against the microfilariae and the adult worms are distinct and separate. The optimal duration of treatment can be roughly estimated in clinical cases, however, by the time of appearance and disappearance of allergic reactions during treatment, since the reactions are thought to denote an effect against the adult worm. These symptoms occur at different times in different individuals. For maximum curative effects it is suggested that treatment be continued for at least 3 weeks after the disappearance of the last systemic reactions occurring during treatment. This would bring the course of treatment to at least three weeks when the only reaction occurred on the first day of treatment, but in many cases further treatment would be indicated, since reactions might not occur and disappear until after one or more weeks of treatment. In cases of clinical filariasis where no reactions occur in the early period of therapy, it is more difficult to estimate the optimum duration of therapy. Such cases may not be sensitized to filarial protein when the adult worms are killed. On the other hand, the absence of any systemic reactions whatever may denote that the adult worms are not being killed, and periods of four to six weeks of therapy may be necessary.
6.Atypical clinical manifestations of filariasis, simulating malaria, arthritis, cutaneous diseases etc. may be encountered in hyper-endemic regions. Since conditions of this sort frequently yield to treatment with Hetrazan they should not be overlooked.
7.In clinical filariasis, the absence of microfilariae in the blood is not a contraindication for treatment; neither is the long duration of the infection nor the degree of elephantiasis. The improvement which occurred in more than 50 per cent of such cases after treatment with Hetrazan demonstrates that filariae were present, and that the death of the worms was followed by a recession of symptoms.
Former resident physician, Berbice Company Ltd., American Cyanamid Company, Kwakwani, British Guiana. Present address: 336 West End Avenue, New York, New York.
Parasitologist, Research Division, Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York.